Pathophysiological consequences of homocysteine excess.

Abstract

Elevated level of the nonprotein amino acid homocysteine (Hcy) is a risk factor for cardiovascular diseases, neurodegenerative diseases, and neural tube defects. However, it is not clear why excess Hcy is harmful. To explain Hcy toxicity, the "Hcy-thiolactone hypothesis" has been proposed. According to this hypothesis, metabolic conversion of Hcy to a chemically reactive metabolite, Hcy-thiolactone, catalyzed by methionyl-tRNA synthetase is the first step in a pathway that contributes to Hcy toxicity in humans. Plasma Hcy-thiolactone levels are elevated in human subjects with hyperhomocysteinemia caused by mutations in CBS or MTHFR genes. Plasma and urinary Hcy-thiolactone levels are also elevated in mice fed a high-methionine diet. Hcy-thiolactone can be detrimental because of its intrinsic ability to form N-Hcy-protein adducts, in which a carboxyl group of Hcy is N-linked to epsilon-amino group of a protein lysine residue. This article reviews recent studies of Hcy-thiolactone and N-Hcy-protein in the human body, including their roles in autoimmune response, cellular toxicity, and atherosclerosis. Potential utility of Hcy-thiolactone, N-Hcy-protein, or anti-N-Hcy-protein autoantibodies as markers of Hcy excess is discussed.

• Authors: Hieronim Jakubowski
• Journal: The Journal of nutrition (J Nutr) Vol. 136 Issue 6 Suppl Pg. 1741S-1749S (06 2006) ISSN: 0022-3166 [Print] United States
• PMID: 16702349 (Publication Type: Journal Article)

Chemical References

• Autoantibodies
• Blood Proteins
• Homocysteine
• Methionine
• homocysteine thiolactone
• Lysine

Topics

• Autoantibodies (immunology)
• Blood Proteins (chemistry, immunology, metabolism)
• Cell Death
• Diet
• Endoplasmic Reticulum (drug effects)
• Homocysteine (analogs & derivatives, blood, metabolism, toxicity)
• Humans
• Hyperhomocysteinemia (complications, physiopathology)
• Lysine (metabolism)
• Methionine (administration & dosage)
• Protein Binding